Dopaminergic grafts in the striatum reduce D1 but not D2 receptor-mediated rotation in 6-OHDA-lesioned rats.

Rats received fetal dopaminergic neuronal grafts in the striatum and/or substantia nigra ipsilateral to a 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). Dopaminergic grafts in the striatum substantially and significantly reduced turning elicited by the selective D1 agonist SKF 38393, but did not reduce turning elicited by the selective D2 agonist LY 171555. Thus, reduced turning in such grafted animals in response to non-selective dopaminergic agonists may be the result of diminished D1 supersensitivity. Fetal dopaminergic grafts in the ipsilateral substantia nigra (SN) did not augment the decreases in turning produced by concomitant ipsilateral dopaminergic grafts in the striatum in response to SKF 38393. LY 171555, D-amphetamine or L-DOPA. Dopaminergic grafts in the SN increased, while dopaminergic grafts in the striatum or in striatum and SN decreased, the facilitatory effect of D-amphetamine on rotation elicited by subsequent injection of dopamine agonists.     

Striatonigral projection neurons contain D1 dopamine receptor-activated c-fos

Dopamine receptor agonists which stimulate the D1 receptor have been shown to activate c-fos in the striatum ipsilateral to a 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. In the present study, striatal neurons ipsilateral to a 6-OHDA lesion of the medial forebrain bundle were retrogradely labelled by injection of the fluorescent tracer Fluoro-Gold into the substantia nigra pars reticulata. Five days later, c-fos was induced in the 6-OHDA-denervated striatum by injection of the selective D1 agonist SKF 38393. C-fos-positive nuclei were frequently found in medium-sized striatal cell bodies labelled with Fluoro-Gold. These results indicate that D1 agonists activate c-fos in medium-sized neurons that project to the substantia nigra pars reticulata.     

Effects of D1 and D2 dopamine receptor stimulation on the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats: D1/D2 coactivation induces potentiated responses

Extracellular single unit recording techniques were used to compare the effects of selective and non-selective dopamine agonists on substantia nigra pars reticulata activity in rats with 6-hydroxydopamine induced lesions of the nigrostriatal dopamine pathway. As previously shown, apomorphine (0.32 mg/kg), a dopamine agonist that interacts with both D1 and D2 dopamine receptor subtypes, produced consistent inhibitions of substantia nigra pars reticulata activity in these animals. The D1-receptor agonist, SKF 38393 (RS-SKF 38393, 10 mg/kg), also induced significant inhibitions in the activity of these neurons in 6-hydroxydopamine lesioned rats, although less consistently than did apomorphine. The effects of SKF 38393 were reversed by the D1-antagonist, SCH 23390. The D2 selective agonist quinpirole was considerably less effective than apomorphine at inhibiting substantia nigra pars reticulata activity at doses up to 1 mg/kg. Since comparable experiments have shown that quinpirole is as effective as apomorphine at producing dopamine D2-autoreceptor-mediated effects on dopamine neuron activity, quinpirole's lack of efficacy in the present study relative to that of apomorphine does not appear to be related to differences in relative potency for central D2-receptors using this route of administration. Rather, the relative effectiveness of SKF 38393 on pars reticulata activity suggests that selective stimulation of D1-receptors is at least, if not more, efficacious than selective stimulation of D2-receptors at inducing alterations in the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats. The simultaneous stimulation of both receptors, however, was considerably more effective than selective stimulation of either receptor subtype: doses of SKF 38393 and quinpirole which had no significant effect on nigral activity when administered alone brought about marked inhibition of the firing of these cells when administered simultaneously. No such inhibition was seen when the inactive enantiomer, S-SKF 38393, was substituted for the racemic form of SKF 38393 in this protocol. These observations in 6-hydroxydopamine lesioned rats support other recent findings indicating that the two dopamine receptor subtypes can interact in a synergistic way to affect basal ganglia output.     

Modulation of dopamine D1-mediated turning behavior and striatal c-fos expression by the substantia nigra

In order to study the possible contribution of the substantia nigra (SN) in the positive interaction between dopamine D₁ receptor agonists and glutamate antagonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, the effect of the D₁ agonist, SKF 38393, was studied in combination with intranigral infusions of glutamate antagonists of the NMDA (MK 801, CPP) or AMPA (NBQX) type of receptor. Local infusion into the SN of the 6-OHDA lesioned side of MK 801, CPP or NBQX at doses inducing no or minimal behavioral effects significantly increased the turning behavior and the expression of c-fos induced, in the lesioned caudate-putamen (CPu), by a parenteral administration of SKF 38393. The same result was obtained after intra-SN infusion of the GABA agonist, muscimol. High doses of MK 801, CPP or muscimol infused into the SN produced intense contralateral turning per se and induced a sparse c-fos expression in the lesioned CPu which was antagonized by parenteral administration of MK 801. The results indicate that a depression of SN pars reticulata efferent neurons potentiates D₁-mediated responses and suggest that this area may play a role in the positive interaction between glutamate antagonists and D₁ receptor agonists. © 1995 Wiley-Liss, Inc.     

The dopamine D1 receptor agonist, but not the D2 receptor agonist, induces gene expression of Homer 1a in rat striatum and nucleus accumbens

Stimulation of dopamine receptors may induce striatal Homer 1a, an immediate-early gene (IEG) that is involved in the molecular mechanism for the signaling pathway of the group I metabotropic glutamate receptors. This study examined the effects of the agonists for dopamine D(1)-like and D(2)-like receptors on gene expression of Homer 1a, in comparison with the IEG c-fos expression, in the discrete brain regions of rats. The D(1)-like agonist SKF38393 (20 mg/kg, s.c.) significantly increased the mRNA levels of Homer 1a in the striatum and nucleus accumbens, but not in the medial prefrontal cortex or hippocampus, 2 h after injection, whereas the D(2)-like agonist quinpirole (1 mg/kg, s.c.) had no significant effect on Homer 1a mRNA levels in any brain region examined. Co-administration of SKF38393 and quinpirole significantly increased Homer 1a mRNA levels in the striatum, nucleus accumbens and hippocampus, while this effect was not significantly greater than that of SKF38393 alone. Any treatment did not affect the mRNA levels of other splicing variants, Homer 1b or 1c. In contrast, combination of both dopamine agonists produced a greater increase than SKF38393 did in the mRNA levels of c-fos in the nucleus accumbens, striatum and substantia nigra. These results suggest that stimulation of D(1)-like receptors, but not D(2)-like receptors, may induce gene expression of Homer 1a in the striatum and nucleus accumbens. However, in contrast to c-fos expression, it is unlikely that co-activation of both D(1)-like and D(2)-like receptors exerts a synergic action on Homer 1a expression in these regions.     

Dopamine D1/5 receptor stimulation induces c-fos expression in the subthalamic nucleus: possible involvement of local D5 receptors

The activity of neurons in the subthalamic nucleus controls various aspects of movement. The present study examined the action of dopamine receptor agonists on c-fos gene expression in the subthalamic nucleus in normal rats. We found that systemic administration of the dopamine D1/5 receptor agonist, SKF 82958 (1 mg/kg), induces c-fos expression in the subthalamic nucleus. In contrast, systemic administration of the dopamine D2/3 receptor agonist, quinelorane (2 mg/kg) had no effect. When combined, SKF 82958 and quinelorane induced c-fos expression in subthalamic neurons that was similar to that found following administration of SKF 82958 alone. We also examined c-fos expression in the substantia nigra pars reticulata, the major projection area for subthalamic neurons, and found that SKF 82958, but not quinelorane, caused an induction of c-fos expression in this area. In order to clarify the mechanisms underlying the SKF 82958-mediated induction of c-fos expression in the subthalamic nucleus and substantia nigra pars reticulata, in situ hybridization for the dopamine D1, D2, D3 and D5 receptor mRNAs was performed. The only significant observation was that D5 receptor mRNA is expressed in subthalamic neurons.The present data show that dopamine, via D1/D5 receptors, upregulates c-fos expression in subthalamic neurons, and that the high expression of D5 receptors in this area might be involved. Taken together, these data suggest that dopamine D1/5 receptors are more important for the action of dopamine in the so-called indirect pathway of the basal ganglia circuitry than what is recognized in current models of basal ganglia organization.     

D1 and D2 dopamine receptor mechanisms in dopaminergic behaviors

SKF 38393, a selective D1 dopamine receptor agonist, was investigated when administered alone and in combination with dopaminergic agonists in animal models of extrapyramidal behavior. SKF 38393 did not induce stereotypy in normal rats but enhanced apomorphine-induced stereotypy in a dose-dependent manner. SKF 38393 also augmented and altered the stereotypic response of dopaminergic agonists (+)-4-propylhydronaphthoxazine quinpirole, and ciladopa. The addition of SKF 38393 with ciladopa changed the behavioral response of ciladopa from a partial to a full agonist. SKF 38393 did not alter locomotor behavior; however, it augmented the stimulatory but not the inhibitory response of apomorphine on locomotion. In unilateral 6-hydroxydopamine-lesioned animals, SKF 38393 caused contralateral rotation that were similar to those of other dopaminergic agonists. The addition of SKF 38393 to both mixed D1/D2 (levodopa, pergolide) and selective D2 (PHNO, quinpirole) dopamine agonists resulted in a synergistic rather than an additive effect. No changes in behavior were observed in rats challenged with apomorphine after being treated 21 days with SKF 38393, PHNO, SKF 38393 plus PHNO, or saline. D1 agonism is capable of augmenting and altering dopaminergic behavior of both mixed D1/D2 and D2 dopamine receptor agonists. A combination of D1 and D2 dopamine agonists may represent optimal drug treatment for Parkinson's disease.     

N-methyl-D-aspartate receptor blockade attenuates D1 dopamine receptor modulation of neuronal activity in rat substantia nigra

It has been proposed that dopamine and glutamate affect basal ganglia output, in part, through interactions between D1 receptors and NMDA receptors. The present study examined whether N-methyl-D-aspartate (NMDA) receptor antagonists affect the neurophysiological responses of substantia nigra pars compacta (SNpc; dopaminergic) and pars reticulata (SNpr; non-dopaminergic) neurons to a systemically administered D1 dopamine agonist in two animals models of Parkinson's disease, reserpine treatment and nigrostriatal lesion. Previous studies using extracellular single unit recording techniques have shown that the D1 dopamine agonist SKF 38393 (10 mg/kg) exerts different effects on the firing rates of SNpr neurons after these two dopamine-depleting treatments, suggesting the involvement of multiple mechanisms. SKF 38393 consistently increased the firing rates of SNpr neurons in rats treated subchronically with reserpine, and markedly decreased SNpr firing rates in rats with nigrostriatal damage. Pretreatment with the non-competitive NMDA antagonist MK-801 (0.15 mg/kg i.v.) blocked, and the competitive NMDA antagonist (±)-CPP (30 mg/kg i.p.) attenuated, the rate effects of SKF 38393 in both dopamine-depleted preparations. SKF 38393 consistently inhibited the firing rate of SNpc dopamine neurons after acute reserpine treatment (10 mg/kg, 4–7 hours), an effect specifically mediated by D1 receptors. Pretreatment with MK-801 (0.1 mg/kg i.v.) or the competitive NMDA antagonist (+)-HA-966 (30 mg/kg i.v.) also effectively attenuated SKF 38393's inhibitory effect on SNpc dopamine neurons. Therefore, NMDA receptor blockade markedly reduces the ability of D1 receptor stimulation to modulate firing rates of both dopaminergic and non-dopaminergic cells in the substantia nigra. Although multiple mechanisms appear to underlie D1-mediated effects on substantia nigra firing rates in reserpine and 6-OHDA-treated rats, these results demonstrate a common dependence on glutamatergic transmission and a permissive role for NMDA receptor activation in the ability of D1 receptor stimulation to both enhance and reduce neuronal activity in the substantia nigra. Synapse 30:18–29, 1998. Published 1998 Wiley-Liss, Inc.     

Intranigral but not intrastriatal microinjection of the NMDA antagonist MK-801 induces contralateral circling in the 6-OHDA rat model

When systemically administered to unilaterally 6-OHDA lesioned rats, the non-competitive antagonists of (NMDA) receptors MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) produces a marked rotation response toward the lesioned side. In addition, the same type of injection in non-denervated rats increases locomotor activity without direction predominance. These findings suggest that MK-801 interacts with the dopaminergic pathway to induce motor activity. However, intracerebral injection of MK-801 (5 μg/0.5 μl) in the substantia nigra pars reticula a (SNr), either on the lesioned side or the intact side, induces a significant circling response, contraversive to the injection side. A similar injection of MK-801 (5 μg/1.0 μl) in the striatum causes no rotation response. These results show that the non-competitive NMDA antagonist can induce motor activity in the presence or in the absence of the dopaminergic pathway and that in the latter case its actions is exerted predominantly at the level of the substantia nigra, perhaps through suppression of the excitatory subthalamic drive.     

Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6-hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration

Systemic administration of the selective D1 agonist, SKF 38393, to rats with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway induces contralateral turning and reduces firing rates of substantia nigra pars reticulata neurons. Previous studies have shown that chronically administered levodopa diminishes the contralateral turning induced by SKF 38393 in these animals. The present study demonstrates that twice daily injections (45-50 mg/kg, i.p.) of levodopa for 19 days also diminishes the effects of SKF 38393 on substantia nigra pars reticulata activity. Concomitant with this change, chronic levodopa injections reversed the lesion-induced supersensitivity of substantia nigra pars reticulata neurons to iontophoresed GABA. Neither of these effects were produced by the continuous infusion of levodopa (90-100 mg/kg/day, i.p. by osmotic pump) for 19 days, a treatment that produces average daily blood levodopa levels similar to those produced by chronic levodopa injection. These results suggest that large variations in circulating levodopa levels in 6-hydroxydopamine lesioned rats may desensitize the behavioral responses to D1 dopamine agonist administration by down-regulating D1 and GABA receptor-mediated mechanisms of basal ganglia output through the substantia nigra pars reticulata.     

D1 Dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjected to neonatal dopaminergic denervation: implications for self-injurious behavior

The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder. Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, L-dihydroxyphenylalanine (L-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The L-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the L-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation: and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.     

The expression of proenkephalin and prodynorphin genes and the induction of c-fos gene by dopaminergic drugs are not altered in the striatum of MPTP-treated mice

Summary The expression of proenkephalin (PENK), prodynorphin (PDYN) and c-fos genes was studied in the striatum of C57B1/6 mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP), which are used as a rodent model of Parkinson's disease (PD). Two weeks after systemic administration of MPTP (2×40 mg/kg, s.c. 18h apart), the lesion of the substantia nigra (SN) could be visualised by loss of the nigral tyrosine hydroxylase (TH) mRNA hybridization signal and by a 91% decrease in striatal dopamine levels. The levels of PENK and PDYN mRNAs were not significantly changed in the striatum of the lesioned mice, as compared to non-treated controls. The induction of the immediate early gene c-fos by the dopamine D₂ receptor antagonist haloperidol was not altered, while the selective D₁ receptor agonist SKF 38393 failed to induce c-fos in the striatum of MPTP-treated mice.These results are in contrast to the data concerning rats with the 6-hydroxydopamine (6-OHDA) lesion of the SN, which serve as another rodent model of PD. In the striata of 6-OHDA-lesioned rats, PENK gene is upregulated, PDYN gene is down-regulated and the induction of c-fos gene by D₂ receptor antagonists is abolished, whereas selective D₁ receptor agonists induce c-fos gene, which does not occur in non-lesioned rats.We presume that the lack of influence of the MPTP lesion in mice on the striatal gene expression was mainly caused by insufficient dopamine depletion in the striatum, which could not be increased in this model. The importance of the changes observed in 6-OHDA-lesioned rats has been discussed in the context of the mouse and primate MPTP models of PD.     

Behavioral effects of fetal substantia nigra tissue grafted into the dopamine-denervated striatum: responses to selective D1 and D2 dopamine receptor agonists

Grafts of fetal ventral mesencephalon/substantia nigra cell suspensions into the dopamine-denervated striatum have been shown to reduce many of the behavioral alterations associated with striatal dopamine depletion. In this report, the behavioral response to amphetamine, apomorphine, the D1 receptor agonist SKF82958, and the D2 receptor agonist LY171555 were tested before and after intrastriatal grafts of fetal substantia nigra, of fetal striatum or no implantation procedure in animals with unilateral dopamine denervation. Grafts of fetal substantia nigra tissue were associated with significant behavioral recovery, as indicated by decreased turning induced by amphetamine (P ≤ 0.005), SKF82958 (P < 0.005), and LY171555 (P < 0.002). These effects were significantly different from the response in animals that did not receive grafts (P < 0.05) and occurred in the absence of decreased apomorphine-induced turning. These data suggest that the response to selective D1 or D2 dopamine receptor agonists is diminished following grafts of fetal dopaminergic tissue and that this behavioral effect is dissociable from the phenomena of behavioral supersensitivity to apomorphine. In a subset of substantia nigra grafted animals, it was found that D1 or D2 dopamine receptor antagonists administered 30 min prior to apomorphine could significantly reduce apomorphine-induced turning.     

Selective modifications in GAD67 mRNA levels in striatonigral and striatopallidal pathways correlate to dopamine agonist priming in 6-hydroxydopamine-lesioned rats

The present study investigated long-term alterations in striatal gene expression after single exposure of unilaterally 6-hydroxydopamine-lesioned rats to different dopamine agonists (priming). Rats were primed with the D1 agonist SKF38393 (10 mg/kg), the D2/D3 agonist quinpirole (0.2 mg/kg), the dopamine precursor L-DOPA (50 mg/kg) or with vehicle (drug-naive), and GAD67, dynorphin and enkephalin mRNAs were evaluated in the striatum by in situ hybridization, 3 days after priming. To evaluate GAD67 mRNA in striatonigral and striatopallidal neurons, identified as enkephalin (-) and (+) neurons, double-labelling in situ hybridization was used. Drug-naive lesioned rats showed an increase in GAD67 mRNA in enkephalin (-) and (+) neurons, an increase in enkephalin and a decrease in dynorphin mRNAs. Priming with either SKF38393 or quinpirole further increased GAD67 mRNA in enkephalin (-) and (+) neurons, however, while SKF38393 produced a high and unbalanced activation toward enkephalin (-) neurons, after quinpirole the increase was of low intensity and similar in the two pathways. Dynorphin mRNA was increased by SKF38393 but not by quinpirole, whereas enkephalin mRNA was not changed by either priming. L-DOPA produced a high and similar increase in GAD67 mRNA in enkephalin (-) and (+) neurons. Priming differentially affected peptides and GAD67 mRNA in striatopallidal and striatonigral neurons depending on the dopamine agonist used. The degree of enduring overactivity of the striatopallidal and striatonigral pathways may be related to the ability of L-DOPA and D1 or D2/D3 receptor agonists to prime motor behavioural responses and to produce dyskinetic side-effects.     

Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors.

The effect of administration of subtype selective dopamine (DA) agonists on the 6-hydroxydopamine (6-OHDA) lesion-induced increase of striatal preproenkephalin (PPE) mRNA was examined by dot-blot hybridization. Eight days following a unilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc), PPE mRNA levels in the ipsilateral striatum were increased approximately two-fold. Administration of the D2 DA agonist, quinpirole, dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. The effect of quinpirole was blocked by coadministration of the D2 DA antagonist eticlopride. In contrast, administration of the D1 DA agonist, SKF 38393, either dose-dependently augmented or had no effect on the 6-OHDA lesion-induced increase in striatal PPE mRNA. In the contralateral striatum, administration of quinpirole decreased PPE mRNA, while administration of SKF 38393 increased PPE mRNA compared to sham lesioned control levels. These data suggest the action of DA at D1 and D2 DA receptors differentially regulates striatal PPE mRNA levels and the apparent inhibition of ENK biosynthesis by DA is mediated via an interaction with D2 DA receptors.     

Reformation of the nigrostriatal pathway by fetal dopaminergic micrografts into the substantia nigra is critically dependent on the age of the host.

The aim of this study was to determine whether the growth of axons along the nigrostriatal pathway from fetal dopamine cells, transplanted into the substantia nigra of young postnatal 6-OHDA-lesioned rats, is dependent on the age of the host brain. Neonatal rats were lesioned bilaterally by intraventricular injection of 6-OHDA at postnatal day 1 (P1) and received grafts of E14 ventral mesencephalon at day 3 (group P3), day 10 (group P10), or day 20 (group P20) into the right substantia nigra. One lesioned group was left untransplanted. Six months after surgery the animals were subjected to analysis of drug-induced rotation following injection of amphetamine, apomorphine, a D1 agonist (SKF38393), or a D2 agonist (Quinpirole). Animals transplanted intranigrally at day 3 and day 10 showed a strong amphetamine-induced rotational bias toward the side contralateral to the transplant. Animals transplanted into substantia nigra at P20, like the lesioned control animals, showed no rotational bias. Apomorphine and selective D1 and D2 agonists induced ipsilateral turning behavior in the P3 and P10 group, but not in the P20 or the lesion control groups. Immunofluorescence histochemistry in combination with retrograde axonal tracing, using FluoroGold injection into the ipsilateral caudate-putamen showed colocalization of tyrosine hydroxylase and FluoroGold in large numbers of transplanted neurons in the animals transplanted at postnatal day 3 and postnatal day 10, which was not observed in the group P20. The lesion control group showed a 90% complete lesion of the TH-positive cells in the substantia nigra while largely sparing the neurons in the ventral tegmental area. The results indicate that intranigral grafts can be placed accurately and survive well within the substantia nigra region at various time points during postnatal development. Furthermore, embryonic dopamine neurons have the ability to extend axons along the nigrostriatal pathway and reconnect with the dopamine-depleted striatum when transplanted at postnatal day 3 and postnatal day 10, but not at postnatal day 20.     

Neurophysiological investigation of effects of the D-1 agonist SKF 38393 on tonic activity of substantia nigra dopamine neurons

The effects of the D-1 agonist SKF 38393 on tonic activity of rat substantia nigra pars compacta dopamine neurons were studied using extracellular, single-unit recording techniques. Unlike nonselective D-1/D-2 dopamine agonists or the D-2 agonist quinpirole, SKF 38393 did not inhibit dopamine neuronal activity when applied iontophoretically or when administered intravenously in doses up to 20 mg/kg to chloral hydrate-anesthetized rats. Moreover, pretreatment with SKF 38393 did not alter the inhibitory response of these neurons to apomorphine or the D-2 agonist quinpirole. However, in locally anesthetized, gallamine-treated, artificially respired rats, dopamine cell activity was significantly altered by i.v. administration of SKF 38393; firing rate increases and decreases were observed. Administration of the inactive enantiomer of SKF 38393, S-SKF 38393, did not induce similar changes in parallel experiments. These results support the idea that unlike D-2 autoreceptor stimulation, D-1 receptor stimulation does not exert a direct local effect on dopamine neurons in the substantia nigra pars compacta and suggest that D-1 receptor stimulation at sites postsynaptic to the dopamine cells may indirectly affect the activity of some dopamine neurons through long-loop feedback mechanisms.     

D1 dopamine receptor-mediated induction of zif268 and c-fos in the dopamine-depleted striatum: Differential regulation and independence from NMDA receptors

Excitatory amino acid afferents from cerebral cortex and dopamine afferents from the substantia nigra synapse on common projection neurons in the striatum. Activation of D1 dopamine receptors increases immediate early gene expression in the striatum and conductance through the N-methyl-d-aspartate (NMDA) receptor. To examine the contribution of NMDA receptor activation to dopamine receptor-mediated responses, we determined the effects of intrastriatal administration of NMDA antagonists on immediate early gene expression in the striatum and rotational behavior induced by stimulation of the D1 receptor in rats with unilateral dopamine depletions. Systemic administration of SKF 38393 increased c-fos and zif268 mRNAs in the striatum and induced contralateral rotation. Intrastriatal infusion of the competitive NMDA receptor antagonist (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid caused a dose-dependent attenuation of SKF 38393-induced rotation and partially decreased c-fos mRNA expression. However, D1-mediated increases in zif268 mRNA were not affected, except by the highest concentration of antagonist used (10 mM). Another competitive antagonist, 2-amino-5-phosphonovaleric acid, had similar effects. Like the competitive antagonists, intrastriatal infusion of the non-competitive NMDA antagonist MK-801 partially decreased c-fos, but not zif268, mRNA in the area around the microdialysis probe. However, unlike competitive antagonists, local infusion of 1 mM MK-801 potentiated D1-mediated increases in c-fos and zif268 mRNAs in lateral striatum. These data suggest that 1) some D1 dopamine receptor-mediated effects on striatal function are independent of ongoing NMDA receptor activation, whereas other effects are at least partially mediated by NMDA receptor activity in the striatum, and 2) competitive and non-competitive antagonists of the NMDA receptor differently affect D1-mediated immediate early gene expression in the striatum. © 1996 Wiley-Liss, Inc.     

Sensitization and conditioned rotation: apomorphine, quinpirole and SKF-38393 compared.

Rats lesioned in one substantia nigra were treated on three consecutive days with the nonselective dopamine agonist, apomorphine (0.05 mg kg-1), the selective D2 agonist, quinpirole (0.025, 0.05, or 0.2 mg kg-1) or the selective D1 agonist, SKF-38393 (2.0, 4.0 or 8.0 mg kg-1). Each of these compounds resulted in acute contralateral rotation which increased significantly upon successive administrations. Two weeks after apomorphine treatment rats exhibited rapid contralateral rotation when placed, undrugged, in the drug-associated environment. Similar undrugged rotation was seen ten weeks after the lower doses of SKF-38393. No evidence of undrugged rotation was seen after quinpirole. The results show that sensitization does not necessarily predict development of a placebo effect, and suggest that persistent motor effects of dopamine agonists are associated with D1 receptor stimulation.